Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells

Kinehara, Yuhei; Nagatomo, Izumi; Koyama, Shohei; Ito, Daisuke; Nojima, Satoshi; Kurebayashi, Ryota; Nakanishi, Yoshimitsu; Suga, Yasuhiko; Nishijima-Futami, Yu; Osa, Akio; Nakatani, Takeshi; Kato, Yasuhiro; Nishide, Masayuki; Hayama, Yoshitomo; Higashiguchi, Masayoshi; Morimura, Osamu; Miyake, Kotaro; Kang, Sujin; Minami, Toshiyuki; Hirata, Haruhiko; Iwahori, Kota; Takimoto, Takayuki; Takamatsu, Hyota; Takeda, Yoshito; Hosen, Naoki; Hoshino, Shigenori; Shintani, Yasushi; Okumura, Meinoshin; Kumagai, Toru; Nishino, Kazumi; Imamura, Fumio; Nakatsuka, Shin‐ichi; Kijima, Takashi; Kida, Hiroshi; Kumanogoh, Atsushi

doi:10.1172/jci.insight.123093

Cited by 32 publications

(26 citation statements)

References 41 publications

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“…7 Recent work has revealed that semaphorins play roles not only in neural guidance but also in immune responses, tumor metastasis, and angiogenesis. [8][9][10] Semaphorin 4D (SEMA4D) was the first semaphorin reported to have a role in the immune system. SEMA4D is expressed on the surface of various types of cells including lymphocytes, neutrophils, platelets, mast cells, and eosinophils.…”

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confidence: 99%

Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis

Tsuda

Nishide

Maeda

et al. 2020

Journal of Allergy and Clinical Immunology

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confidence: 99%

Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis

Tsuda

Nishide

Maeda

et al. 2020

Journal of Allergy and Clinical Immunology

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“…Existing investigations have unveiled that SEMA7A acts as an essential participator in integrin‐mediated signalling and exerts vital function on cell migration . Also, SEMA7A has been previously demonstrated to facilitate ERK activation in lung adenocarcinoma, while ERK signalling is a well‐identified pathway in cancer development . Therefore, we speculated that SEMA7A might contribute to PC cell proliferation and migration by similar manners.…”

Section: Discussionmentioning

confidence: 99%

LncRNA LOXL1‐AS1/miR‐28‐5p/SEMA7A axis facilitates pancreatic cancer progression

Liu

Guo

et al. 2019

Cell Biochemistry & Function

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Pancreatic cancer (PC), one of the most aggressive and lethal human malignancies, is associated with a deplorable prognosis despite progressive therapeutic strategies.Emerging evidence manifests that miR-28-5p is involved in several cancers, and its descending expression is associated with poor prognosis. Nevertheless, the function of miR-28-5p in PC remains unclear. Thus, the underlying regulatory mechanism of miR-28-5p in PC is urgent to be clarified. In the present study, we first recognized miR-28-5p was downregulated in PC, and miR-28-5p overexpression inhibited cell proliferation and migration in PC. Then miR-28-5p was verified to act as a molecular sponge of LOXL1-AS1. Therefore, the function of LOXL1-AS1 was further explored in PC, presenting that LOXL1-AS1 suppression inhibited cell proliferation and migration. What is more, SEMA7A was found to be a target gene for miR-28-5p and was upregulated in PC. In addition, LOXL1-AS1 could positively regulate SEMA7A expression while miR-28-5p could negatively regulate SEMA7A expression. According to rescue experiments, SEMA7A overexpression partially neutralized LOXL1-AS1 silence-mediated inhibitory function on progression in PC. Taken together, all the data demonstrated that LOXL1-AS1/miR-28-5p/SEMA7A axis facilitated pancreatic cancer progression, which may be regarded as an innovative therapeutic target for PC treatment.Significance of the study: Our findings constitute the first report to delineate that lncRNA LOXL1-AS1/miR-28-5p/SEMA7A axis facilitates PC progression. According to our experimental results, we found the expression of miR-28-5p was downregulated in PC cells and miR-28-5p overexpression inhibited cell proliferation and migration in PC. LOXL1-AS1 could sponge miR-28-5p and then upregulate the expression of SEMA7A. Thus, LOXL1-AS1/miR-28-5p/SEMA7A axis facilitated PC progression. This initially proposed point might provide a novel molecular target for PC treatment.

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“…It is also possible that SEMA7A may promote resistance to current therapies for breast cancer. For example, it has been shown that SEMA7A promotes resistance to EGFR targeted therapies in lung cancer(53). Interestingly, it has shown that estrogen and/or progesterone promote SEMA7A expression in the hypothalamus, suggesting that hormone signaling may promote elevated levels of SEMA7A in breast cancers(54).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, similar to SEMA7A, EMT induced transcription factors such as Slug and and Zeb1 regulate pro-survival pathways, which results in resistance to chemotherapeutic and targeted therapy treatments. Of note, SEMA7A promotes resistance to EGFR-targeted tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma 41 and lung cancer cells with increased expression levels of EMT markers are less sensitive to TKIs 42,43 . Interestingly, SEMA7A has previously been directly linked to EMT in a Ras-dependent model of murine mammary carcinoma in a TGFβ inducible manner where the authors show that TGFβ is unable to induce an EMT without SEMA7A 29 .…”

Section: Discussionmentioning

confidence: 99%

Postpartum breast cancer progression is driven by semaphorin 7a mediated invasion and survival

Tarullo

Hill

Hansen

et al. 2019

Preprint

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Breast cancer (BC) remains the second leading cause of cancer related deaths in women in the US --mainly due to metastatic disease. Thus, understanding how BC progresses is of the utmost importance to developing new strategies to block metastasis. Young women diagnosed with BC generally have poor prognosis due to increased rates of metastasis. Additionally, women who are within 5 years of most recent child-birth at diagnosis are ~3 times more likely to develop metastasis than age and stage matched nulliparous women. We define these cases as postpartum breast cancers (PPBC) and propose that the unique biology of the postpartum mammary gland drives tumor progression and metastasis. Semaphorin 7a (SEMA7A) is a unique member of the Semaphorin family as it is the only GPI-anchored member that can be shed into the extracellular environment. Our published results show that SEMA7A expression is associated with decreased overall survival in BC patient cohorts and revealed roles for SEMA7A in breast tumor cell growth, motility, invasion, and tumor associated-lymphangiogenesis all of which are also increased in pre-clinical models of PPBC. However, whether primary SEMA7A driver PPBC progression remains largely unexplored. We utilized a pre-clinical of PPBC with breast cancer cells where we silenced or overexpressed SEMA7A. Our results show that silencing of SEMA7A decreases tumor growth in postpartum hosts while overexpression increases growth in nulliparous hosts to rates closer to those observed in postpartum hosts. Further, we show that SEMA7A effects multiple pro-metastatic tumor attributes such as cell survival, tumor associated COX-2 expression, fibronectin deposition, and fibroblast-mediated collagen deposition in the tumor microenvironment regardless of whether the host is nulliparous or postpartum. Finally, we show that co-expression of SEMA7A/Collagen/COX2/FN mRNA predicts for increased metastasis in breast and ovarian cancer cohorts. These studies suggest SEMA7A as a key mediator of general BC progression and that targeting SEMA7A alone or in combination may open avenues for novel therapeutic strategies to prevent BC progression to metastasis. INTRODUCTION:Postpartum breast cancers (PPBC), or breast cancers diagnosed within 5-10 years of last childbirth, are nearly three times as likely to become metastatic and result in death from breast cancer 1-3 . Specifically, PPBC patients diagnosed within five years of last competed pregnancy exhibit 70% distant metastasis free five-year survival (DMFS) rates 1 that are further decreased to 50% after ten years 2 . Using this definition, PPBC may account over half of breast cancers diagnosed in women aged <45 in two independent cohorts. Using a pre-clinical model of PPBC we have shown that noninvasive breast tumor cells, MCF10DCIS, become invasive and metastatic if they are implanted into mouse mammary tissues during the normal physiological process of postpartum mammary gland involution 4 . The MCF10DCIS model closely resembles ductal carcinoma in situ (DCIS) and progresse...

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Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells

Cited by 32 publications

References 41 publications

Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis

Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis

LncRNA LOXL1‐AS1/miR‐28‐5p/SEMA7A axis facilitates pancreatic cancer progression

Postpartum breast cancer progression is driven by semaphorin 7a mediated invasion and survival

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